Project Summary Autism spectrum disorders (ASD) are the cause of large health-related and economical costs in the U.S. Thus, interventions that relieve symptoms for ASD patients are urgently needed. There are currently no treatments approved by the Food and Drug Administration for ASD. The development of novel therapeutic interventions will require early and reliable biomarkers and improved understanding of the underlying ASD pathophysiology. Most of the research on ASD so far has focused on mechanisms and circuits specific to the central nervous system with little attention to the contributions of abnormal signaling in the peripheral nervous system and spinal cord to the pathophysiology and core symptoms of ASD. Critically, most ASD patients exhibit enhanced responses to sensory stimuli, including tactile stimuli. Moreover, the degree of tactile hypersensitivity is strongly correlated with increased anxiety behaviors and social-behavior deficits observed in ASD. However, there are currently no neurophysiologic indices of tactile hypersensitivity and its contribution to dysfunction of brain networks. In cohorts of 40 ASD young adults, and 40 neurotypical young adults, we will compare the responses to paired associative stimulation (PAS) of the median nerve and the primary motor cortex between individuals with ASD and the control group ? this will serve as a primary measure of the lasting effects on cortical cuntion that aberrant (pathologically heightened) peripheral signaling may have in ASD. Second, we will examine the correlation between the extent of abnormal PAS response in the ASD group and the degree of tactile hypersensitivity as objectively quantified by tactile prepulse inhibition (PPI) and mechanical detection threshold with von Frey fibers. Third, we will test the contribution of the common Val66Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene to PAS measures. Each participant will undergo 4 visits, including two visits for quantitative tactile assessments and two visits for assessment of PAS-induced plasticity. All participants will undergo baseline assessment, including detailed screening, physical/neurological exam, neuropsychological assessment, and assessment of saliva samples for the BDNF SNP to explore predictors of PAS response. The proposed studies will be the first to validate well-formulated hypotheses from animal ASD research with PAS measures of tactile hypersensitivity. Favorable results from proposed experiments will validate standardized tools as biomarkers of tactile hypersensitivity in ASD and will provide measures of target engagement in future therapeutic trials aimed at improving tactile hypersensitivity and associated anxiety and social behavior deficits among ASD patients.